EP0245855B1 - Sucralfate preparations for application on esophagus mucosa - Google Patents

Sucralfate preparations for application on esophagus mucosa Download PDF

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Publication number
EP0245855B1
EP0245855B1 EP87106961A EP87106961A EP0245855B1 EP 0245855 B1 EP0245855 B1 EP 0245855B1 EP 87106961 A EP87106961 A EP 87106961A EP 87106961 A EP87106961 A EP 87106961A EP 0245855 B1 EP0245855 B1 EP 0245855B1
Authority
EP
European Patent Office
Prior art keywords
sucralfate
suspension
esophagitis
water
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP87106961A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP0245855A3 (en
EP0245855A2 (en
Inventor
Kouji Ishihara
Toshichika Ogasawara
Kazuo Igusa
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chugai Pharmaceutical Co Ltd
Original Assignee
Chugai Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chugai Pharmaceutical Co Ltd filed Critical Chugai Pharmaceutical Co Ltd
Priority to AT87106961T priority Critical patent/ATE84218T1/de
Publication of EP0245855A2 publication Critical patent/EP0245855A2/en
Publication of EP0245855A3 publication Critical patent/EP0245855A3/en
Application granted granted Critical
Publication of EP0245855B1 publication Critical patent/EP0245855B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • This invention relates to sucralfate preparations for application on esophagus mucosa.
  • sucrose sulfate ester Conventionally known as sucralfate
  • sucralfate an aluminum salt of sucrose sulfate ester
  • DE-A-34 30 809 describes sucralfate preparations in form of suspensions comprising 1 to 5% by weight xanthan gum and 1-12.5% by weight of a peptizer.
  • the subject-matter of the EP-A-0 136 100 is to provide a suspension for treatment of ulcerative conditions comprising a pharmaceutically effective amount of sucralfate and a pharmaceutically acceptable suspending agent and forming a viscous mass when added to 0.2 to 1N hydrochloric acid.
  • Sucralfate is characterized by anti-pepsin and anti-acid effects in that it binds to the pepsin and acids in gastric juice, which are two agents that attack the ulcer-affected area of digestive tracts, and thereby inhibits their activities directly.
  • Sucralfate is also characterized by its ability to protect the mucosa in that it forms a sucralfate coat on the mucosa of the digestive tract and protects it from the attacking agents. These effects combine to provide sucralfate with high anti-ulcer activities. It has also been found that sucralfate is effective in revascularization and in accelerating the growth of regenerated mucosa, and hence is considered to have a great potential for use in promoting the healing of ulcers.
  • Sucralfate has an ability to selectively bind to the ulcer-affected mucosa of the digestive tract rather than the normal mucosa of the digestive tract and form a protective coat against the invasion of attacking agents. This ability is the most characteristic feature of sucralfate, not found in other anti-ulcer treatments.
  • the esophagus differs in function from other digestive organs, in that it is not concerned with the digestion of foods or the absorption of the nutrients; but instead plays an important role in transporting foods from the oral cavity to the intraperitoneal digestive tract. In a normal person the digestive liquid which has been regurgitated from the stomach to the esophagus may be returned immediately by the action of vermiculation of the esophagus.
  • regurgitational esophagitis is considered to be caused by various factors which have an affect upon each other. It is also known that this type of regurgitational esophagitis repeatedly results in recrudescence and relapse of diseases, and that a long period of time is required for therapy and observation in the subsequent curing process. Further, this disease is associated with deformation and stricture of the esophagus. For these reasons, this type of esophagitis is recognized to be very difficult to cure and has been mainly treated by surgical means.
  • nonserious regurgitational esophagitis may usually be cured by alimentary therapy and/or by controlling the patient's daily routine.
  • simple alimental therapy is not sufficient to cure the disease effectively and a more positive treatment using drugs is required.
  • a pharmaceutical preparation be orally administered and adhered on inflammatory sites in wet tissue such as those formed in esophageal mucosa
  • the administration of a preparation in the form of tablet, troche or sublingual tablet is unable to readily provide such desired effects as binding or adhering of the pharmaceutical preparation to the inflammatory sites because a patient often swallows or crunches the solid preparation.
  • these problems can not be solved by simply increasing the dose level of the drug.
  • the administration of an effective component in the form of powder will not provide the desired effects for several reasons, typically because the administration of a powdery preparation is associated with pain.
  • a preparation in the form of a suspension has advantages in that the dose level can be easily controlled, and in that it is a very easy form for oral dosage.
  • the inventors of this application extensively studied the dosage form of sucralfate in order to fully develop its above-mentioned advantages by the use of a suspension dosage form.
  • a suspension having a viscosity of higher than 500 mPas [centipoise (cP)] is difficult to use clinically, and that it is preferable to use a suspension with a viscosity of lower than 50 mPas (cP), especially from the organoleptic viewpoint.
  • sucralfate preparations with less than 500 mPas (cP) at 20°C.
  • These preparations include suspensions without any suspension stabilizer or thickener; suspensions containing a water-insoluble or water soluble polymeric substance as a suspension stabilizer or thickener; suspensions containing a thickener such as glycerine, sucrose or sorbitol; suspensions formulated by using sucralfate having particles of predetermined and relatively uniform sizes; suspensions containing various additives such as sugars, salts, acids or bases; suspensions having various concentrations of suspended particles; suspensions containing a surfactant for the purpose of changing their physical properties; suspensions prepared by varying the conditions of a homogenizing mixer; and suspensions using the above-mentioned conditions with a different suspension medium.
  • suspensions were tested with respect to their selective binding to the ulcerated or inflammatory sites of esophageal mucosa.
  • the suspension was forcefully administered through a probe into the esophagus of rats in which esophagitis had been artificially induced or which have not been treated.
  • the selective binding of sucralfate to ulcerated or inflammatory sites was determined by measuring the amount of sucrose sulfate and aluminum adhered to each of the ulcerated or inflammatory sites as well as sites which had not been ulcerated or were not inflammatory with respect to the resected pieces of mucosa having the same and predetermined size.
  • the rats were killed and the pieces of mucosa were prepared.
  • the amount of each of aluminum and sucrose adhered on the samples was determined by the methods of Okamura et al., Bull. Chem. Soc. Japan, 31,783 (1958) and the method of Nagashima et al., "Arzneim-Forsch. 29, 1668 (1979)", respectively.
  • sucralfate effectively adheres to inflammatory sites, it is necessary that it is suspended in an aqueous solution or suspension of one or more water-soluble or water-insoluble, natural or synthetic or semi-synthetic polymeric substances and having a viscosity of from 1,000 to 5,000 mPas (cP).
  • the present invention relates to a sucralfate preparation in the form of a suspension comprising sucralfate suspended in an aqueous solution or suspension of one or more water-soluble or water-insoluble cellulose substances as a suspending agent or thickening agent characterized in that the cellulose suspending agent or thickening agent comprises at least one of crystalline cellulose, hydroxyethylcellulose or hydroxypropylmethylcellulose and which is added in an amount that the suspension has a viscosity of from 1,000 to 5,000 mPas (centipoise) at 20°C.
  • the cellulose substances which are useful in this invention include water-soluble cellulose substances such as crystalline cellulose, carboxymethylcellulose and calcium carboxymethylcellulose, methylcellulose (substitution degree: 1.6 - 2), ethylcellulose (substitution degree: 1 - 1.5), propylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxyethylpropylcellulose, hydroxypropylmethylcellulose, carboxymethyl-starch, carboxymethylethylcellulose and carboxymethylhydroxyethylcellulose.
  • water-soluble cellulose substances such as crystalline cellulose, carboxymethylcellulose and calcium carboxymethylcellulose, methylcellulose (substitution degree: 1.6 - 2), ethylcellulose (substitution degree: 1 - 1.5), propylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxyethylpropylcellulose, hydroxypropylmethylcellulose, carb
  • the amount of polymer to be used in this invention may be determined based on the specific polymer used and the viscosity of the suspension.
  • one or more appropriate additive such as sweeteners, flavoring, preservatives or excipients can be incorporated in the suspension of this invention. These additives may be used by selecting the species, amount, and incorporation manner in accordance with conventional practice for formulation of pharmaceutical preparations.
  • Crystalline cellulose (sold under the trade name of Avisel RC-591NF: 10 g) was preliminarily dispersed in distilled water in an agitating and homogenizing mixer. To the dispersion was slowly added DL-alanine (5 g) and then sucralfate (50 g) while stirring. After a preservative (0.4 g) had been added and the mixture stirred, water was added to bring the total volume to 500 ml to give a suspension which was used as a test sample.
  • Hydroxypropylmethylcellulose (7.5 g) was preliminarily dispersed in distilled water in an agitating and homogenizing mixer. To the dispersion was slowly added DL-alanine (5 g) and then sucralfate. After further adding a 70% D-sorbitol aqueous solution (25 g) and a preservative (0.4 g) to the mixture and stirring it, the mixture was treated as in Example 1 to give a suspension which was used as a test sample.
  • Hydroxyethylcellulose (10 g) was dissolved in water. To the solution was slowly added DL-alanine (5 g) and, then, sucralfate (50 g) while stirring in a mixer. Then, sucrose (25 g) and a preservative (0.4 g) were added to the mixture which was treated as shown in Example 1 to give a suspension which was used as a sample of this invention.
  • Wistar-strain male rats weighing about 200 g were caused to fast for 48 hours, their abdomen opened, and pylorus ligated.
  • atropine 0.2 mg/kg
  • 2 ml of 1N hydrochloric acid were orally administered by use of a cannula to develop esophagitis with remarkable degeneration of mucosal epithelium, hemostatis and cellular infiltration.
  • the sample or control which was prepared by each of the Examples was forcefully administered to the esophagitis-induced rats through a cannula.
  • the test animals were divided into groups of six members each and the sample or control was administered in a dose of 0.5 ml per head in terms of suspension, or 50 mg per head in terms of sucralfate.
  • the rats were killed and the quantity of each of aluminum and sucrose sulfate ester adhered to the inflammatory sites of esophagitis was determined.
  • Table 1 The results are shown in Table 1 below. As is clear from the test results, the values of aluminum and the ester with respect to the sample suspension were larger than those of the control. Table 1 Examples Test suspension Viscosity (cP, 20°C) mPas Sucrose sulfate ester ( ⁇ mol/cm2) Aluminum ( ⁇ mol/cm2) 1 sample 1080.0 1.458 2.458 control 7.5 0.066 0.115 2 sample 1502.5 1.619 2.421 control 8.3 0.019 0.043 3 sample 2030.0 1.589 2.356 control 10.6 0.008 0.017

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Inorganic Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Saccharide Compounds (AREA)
  • Steroid Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Dental Preparations (AREA)
  • Materials For Medical Uses (AREA)
EP87106961A 1986-05-16 1987-05-14 Sucralfate preparations for application on esophagus mucosa Expired - Lifetime EP0245855B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT87106961T ATE84218T1 (de) 1986-05-16 1987-05-14 Sucralfatpraeparate zur anwendung fuer die speiseroehrenschleimhaut.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP11068686 1986-05-16
JP110686/86 1986-05-16

Publications (3)

Publication Number Publication Date
EP0245855A2 EP0245855A2 (en) 1987-11-19
EP0245855A3 EP0245855A3 (en) 1988-06-08
EP0245855B1 true EP0245855B1 (en) 1993-01-07

Family

ID=14541876

Family Applications (1)

Application Number Title Priority Date Filing Date
EP87106961A Expired - Lifetime EP0245855B1 (en) 1986-05-16 1987-05-14 Sucralfate preparations for application on esophagus mucosa

Country Status (14)

Country Link
EP (1) EP0245855B1 (no)
JP (1) JP2583054B2 (no)
KR (1) KR950005870B1 (no)
AT (1) ATE84218T1 (no)
AU (1) AU594765B2 (no)
CA (1) CA1307465C (no)
DE (1) DE3783390T2 (no)
DK (1) DK164199C (no)
ES (1) ES2053465T3 (no)
FI (1) FI91598C (no)
HK (1) HK65293A (no)
NO (1) NO175516C (no)
SG (1) SG64593G (no)
ZA (1) ZA873496B (no)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6699315B2 (en) 2000-11-28 2004-03-02 Fmc Corporation Edible PGA coating composition
US6723342B1 (en) 1999-02-08 2004-04-20 Fmc Corporation Edible coating composition

Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK505488D0 (da) * 1987-12-21 1988-09-09 Bar Shalom Daniel Middel og anvendelse af samme
US5908836A (en) * 1987-12-21 1999-06-01 Bar-Shalom; Daniel Protecting skin from radiation damage using sulphated sugars
US5709873A (en) * 1988-02-26 1998-01-20 Niels Bukh A/S Method of treating conditions of teeth and their supporting tissue
DK505588D0 (da) * 1988-02-26 1988-09-09 Jesper Hamburger Middel og anvendelse af samme
JP2735559B2 (ja) * 1988-03-02 1998-04-02 中外製薬株式会社 懸濁液
US4975281A (en) * 1989-01-30 1990-12-04 E. R. Squibb & Sons, Inc. Anti-ulcer composition
US5618798A (en) * 1989-04-20 1997-04-08 Bar-Shalom; Daniel Use of sucralfate to treat baldness
IE903302A1 (en) * 1989-09-15 1991-04-10 Pehrom Pharmaceutical Corp Topical preparation for treatment of aphthous ulcers and¹other lesions
DE69132837T2 (de) * 1990-08-31 2002-04-11 Chugai Seiyaku K.K., Tokio/Tokyo Herstellung einer vorratslösung von in wasser suspendiertem sucralfat
FI924470A0 (fi) * 1992-10-05 1992-10-05 Orion Yhtymae Oy Sukralfatpreparat
IT1264546B1 (it) * 1993-07-30 1996-10-02 Lisapharma Spa Composizione farmaceutica ad attivita' antiacida in forma di sospensione a base di gel di sucralfato
US5783568A (en) * 1994-06-10 1998-07-21 Sugen, Inc. Methods for treating cancer and other cell proliferative diseases
US6319513B1 (en) 1998-08-24 2001-11-20 The Procter & Gamble Company Oral liquid mucoadhesive compounds
US6432448B1 (en) * 1999-02-08 2002-08-13 Fmc Corporation Edible coating composition
WO2002004411A1 (en) 2000-07-07 2002-01-17 The Administrators Of The Tulane Educational Fund Methods for protection of stratified squamous epithelium against injury by noxious substances and novel agents for use therefor
WO2014151565A1 (en) 2013-03-15 2014-09-25 The Brigham And Women's Hospital, Inc. Compounds to modulate intestinal absorption of nutrients
JP6365235B2 (ja) 2014-10-28 2018-08-01 ライオン株式会社 液状組成物
EP3352738B1 (en) 2015-09-24 2024-01-17 The Brigham and Women's Hospital, Inc. Water-activated mucoadhesive compositions to reduce intestinal absorption of nutrients
JP2017178881A (ja) * 2016-03-31 2017-10-05 小林製薬株式会社 経口組成物
KR101837104B1 (ko) * 2017-04-14 2018-03-09 한국프라임제약주식회사 수크랄페이트 합성 방법 및 이에 의한 수크랄페이트
US20220175885A1 (en) * 2019-03-20 2022-06-09 Reponex Pharmaceuticals A/S Targeting biological agents to mucosal defects of the gastrointestinal tract

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0136100A2 (en) * 1983-09-02 1985-04-03 Marion Merrell Dow Inc. Sucralfate suspension for use in treating ulcers

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3432489A (en) * 1965-11-05 1969-03-11 Chugai Pharmaceutical Co Ltd Disaccharide polysulfate aluminium compound and method
DE3315800A1 (de) * 1983-04-30 1984-10-31 Merck Patent Gmbh, 6100 Darmstadt Verfahren zur herstellung eines granulats
DE3430809A1 (de) * 1984-08-22 1986-03-06 Merck Patent Gmbh, 6100 Darmstadt Sucralfat-suspension

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0136100A2 (en) * 1983-09-02 1985-04-03 Marion Merrell Dow Inc. Sucralfate suspension for use in treating ulcers

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6723342B1 (en) 1999-02-08 2004-04-20 Fmc Corporation Edible coating composition
US6699315B2 (en) 2000-11-28 2004-03-02 Fmc Corporation Edible PGA coating composition

Also Published As

Publication number Publication date
AU594765B2 (en) 1990-03-15
CA1307465C (en) 1992-09-15
FI91598B (fi) 1994-04-15
EP0245855A3 (en) 1988-06-08
NO175516B (no) 1994-07-18
KR950005870B1 (ko) 1995-06-02
JPS63107934A (ja) 1988-05-12
FI872169A (fi) 1987-11-17
DE3783390D1 (de) 1993-02-18
HK65293A (en) 1993-07-16
NO872002D0 (no) 1987-05-14
FI872169A0 (fi) 1987-05-15
AU7279587A (en) 1987-11-19
JP2583054B2 (ja) 1997-02-19
ATE84218T1 (de) 1993-01-15
NO175516C (no) 1994-10-26
ES2053465T3 (es) 1994-08-01
DK164199B (da) 1992-05-25
SG64593G (en) 1993-08-06
FI91598C (fi) 1994-07-25
DK164199C (da) 1992-10-19
KR890001515A (ko) 1989-03-27
DE3783390T2 (de) 1993-05-06
DK243587D0 (da) 1987-05-13
NO872002L (no) 1987-11-17
EP0245855A2 (en) 1987-11-19
DK243587A (da) 1987-11-17
ZA873496B (en) 1987-11-09

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